Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects.
Both duplications encompassing SOX3 and loss-of function mutations in SOX3 have been reported in a minor portion of X-linked isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD) patients with or without mental retardation.
In humans, over- and underdosage of SOX3 is associated with X-linked hypopituitarism with variable phenotypes ranging from isolated GH deficiency (GHD) to panhypopituitarism, with or without mental retardation and, in most cases, with reported pituitary imaging, an ectopic/undescended posterior pituitary.
Both overdosage of SOX3, as a result of gene duplication, and loss of function resulting from expansion of the first polyalanine (PA) tract are associated with variable degrees of hypopituitarism, with or without mental retardation.
We conclude that both over- and underdosage of SOX3 are associated with similar phenotypes, consisting of infundibular hypoplasia and hypopituitarism but not necessarily MR.